African Americans are twice as likely to develop type 2 diabetes (T2DM) as Caucasian Americans, and have 1.2-5 times the rate of diabetic complications. We have carried out the first large-scale genome-wide scan for African American T2DM using 636 affected sibling pairs from 251 families. We detected a linkage peak on chromosome 6q23-q27, LOD 2.08 163.5cM from the p telomere. Under models of heterogeneity, this linkage peak rises to 3.00. This region has provided modest evidence for linkage to T2DM and related phenotypes in other populations. Our goal is to use a positional cloning approach to identify variants in genes that contribute to T2DM susceptibility in the African American population. We will conduct comprehensive analyses of existing data, including adjustments for BMI, age at diagnosis, duration of disease, gender, and exploration of interactions using epistasis models and a genome x genome approach. The region of linkage will be refined by genotyping additional microsatellites, and an evaluation of a limited number of candidate genes initiated. We will embark upon construction of a dense SNP map to facilitate the identification of minimal haplotypes associated with African American T2DM, followed by a focused search for genes contributing to diabetes.